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Monday, March 1, 2010

Evolution for real, and for keeps

Of all the things we should be spending research funds furiously on, infectious disease should be at or near the top of the list. Yet another story has appeared on the proliferation of antibiotic resistant species that are causing death and disease, mainly in hospital patients at present. But there's no reason to expect this to stay contained. And here we face real instances of genetic and evolutionary determinism. Since proper nutrition and exercise would also be a way to avoid massive numbers of otherwise early deaths, because hale people have at least better chances of surviving infection, we should refocus effort, away from luxury and made-up 'genetic' disease to these major societal problems.

There is, in fact, evidence that an increasing number of supposedly old-age, lifestyle-related diseases are going to turn out to be related to infection after all--either directly, or indirectly. Here we are learning from many avenues of research, including, yes we're free to acknowledge it, from GWAS approaches (case-control studies that searched for regions of the genome whose variation was associated with risk). Some cancers like stomach and cervical, among others, turn out to be due largely to bacterial or viral infection. Some heart disease is like that, too. But the genes identified by some of the more successful GWAS turn out to have connection with inflammatory gene networks. These include problems with intestinal, eye, and even psychiatric functions.

Direct infection may cause the disorder (the GWAS would be identifying genes whose variation somewhat protects, or makes one somewhat more susceptbible to the disorder). Or in a substantial number of diseases, the effect may be indirect: autoimmune diseases in which the immune system, after a real infection, mistakes your own cells for attacking bacteria; or perhaps infection in which the successful immune response then leads to chronic inflammation that itself may be damaging (these are called autoimmune disorders).

In genetic studies susceptibility variants may be brought detectably to the fore by the strong point-cause effects of infection, and that could explain why a disproportionate fraction of detected genes--of GWAS genomic 'hits'--seem to be involve the immune system. Since the susceptibility variants are not nearly fixed in the population--it's the fact of their variation that makes them detectable by association studies--they are probably not the result of a history of widespread or very serious infection with strong natural selection effects. And the signals usually only account for a small fraction (usually very small) of what are complex traits involving many contributing genes and environmental exposures.

But antibiotic resistance is a kind of classic Darwinism. Pathogens have simple genomes, huge population sizes, and rapid generational turnover. Antibiotics slam them with a sledgehammer kind of very strong selective effect. This is a cocktail of factors ready-made for the rapid evolution of the favored few--the lucky bacteria or viruses whose makeup makes them resistant. The wipe-out of their susceptible peers leaves an open field for the resistant ones to proliferate, and the rapid turnover and great population growth rate favors quick fixation of the new genetic variant in the population. Further, the dense population of very similar food items (humans, particularly hospitalized humans, at least so far) favors rapid growth and spread of the pathogen population, too.

Here is where evolutionary and genetic theory meet in classically relevant ways. The standard deterministic models work well, because the signal can be so much stronger than the statistical 'noise' of chance events in the lives and times of individual bacteria.

Whereas genetic susceptibility to disease in the host (us) is fairly similar in most individuals, we represent in a sense a standing target for the bugs to adapt to. We do have an immune system designed to evolve as fast as microbes do (it's called our 'adaptive' immune system, and is too intricate to go into here--but it is covered in our book and of course in many sites on the web), even this system may be unable to cope with the hardy pathogens that evolve in survivors of our antibiotic assault.

For whatever reason even the adaptive immune system in vertebrates, including humans, may not have been exposed to environments so changeable as those we're likely to subject ourselves to in the near future if we're not careful. Whatever the reason, if we're slow to respond we're going to teach ourselves a clear lesson in evolutionary genetics.

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